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Clinical Cancer Research : An Official... Aug 2021Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated...
PURPOSE
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
PATIENTS AND METHODS
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant (m) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
RESULTS
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months [95% confidence interval (CI), 11.2-40.8] for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
CONCLUSIONS
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m LGG.
Topics: Adolescent; Adult; Aged; Brain Neoplasms; Diamines; Disease Progression; Female; Glioma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Pyridines; Young Adult
PubMed: 34078652
DOI: 10.1158/1078-0432.CCR-21-0611 -
Autophagy Feb 2023Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore,...
Impaired mitophagy is a primary pathogenic event underlying diverse aging-associated diseases such as Alzheimer and Parkinson diseases and sarcopenia. Therefore, augmentation of mitophagy, the process by which defective mitochondria are removed, then replaced by new ones, is an emerging strategy for preventing the evolvement of multiple morbidities in the elderly population. Based on the scaffold of spermidine (Spd), a known mitophagy-promoting agent, we designed and tested a family of structurally related compounds. A prototypic member, 1,8-diaminooctane (VL-004), exceeds Spd in its ability to induce mitophagy and protect against oxidative stress. VL-004 activity is mediated by canonical aging genes and promotes lifespan and healthspan in . Moreover, it enhances mitophagy and protects against oxidative injury in rodent and human cells. Initial structural characterization suggests simple rules for the design of compounds with improved bioactivity, opening the way for a new generation of agents with a potential to promote healthy aging.
Topics: Aged; Animals; Humans; Caenorhabditis elegans; Mitophagy; Diamines; Autophagy; Oxidative Stress
PubMed: 35579620
DOI: 10.1080/15548627.2022.2078069 -
Singapore Medical Journal Jan 2023With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple... (Review)
Review
With the increasing availability of genetic tests, more doctors are offering and ordering such tests for their patients. Ordering a genetic test appears to be a simple process of filling in paperwork, drawing 3 mL of blood in an ethylenediaminetetraacetic acid tube and receiving a test report. This is identical to sending off a full blood count. However, it is far more complex than that. There are many potential pitfalls, as shown by the increasing number of complaints and lawsuits filed against doctors and allied health staff. Furthermore, clinical genetics involves more than just ordering tests; in fact, focusing on genetic tests alone is a potential pitfall. In this review, we discuss the common pitfalls in clinical genetics and how doctors can avoid these pitfalls to ensure patient safety and to safeguard their practice.
Topics: Humans; Edetic Acid; Fenbendazole; Patient Safety; Physicians
PubMed: 36722517
DOI: 10.4103/singaporemedj.SMJ-2021-329 -
The Journal of Biological Chemistry Oct 2021
Review
Topics: Aniline Compounds; Animals; Calcium; Egtazic Acid; Fluorescent Dyes; Humans; Optical Imaging; Xanthenes
PubMed: 34508781
DOI: 10.1016/j.jbc.2021.101181 -
Applied and Environmental Microbiology Nov 2020Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With... (Review)
Review
Diamines are important monomers for polyamide plastics; they include 1,3-diaminopropane, 1,4-diaminobutane, 1,5-diaminopentane, and 1,6-diaminohexane, among others. With increasing attention on environmental problems and green sustainable development, utilizing renewable raw materials for the synthesis of diamines is crucial for the establishment of a sustainable plastics industry. Recently, high-performance microbial factories, such as and , have been widely used in the production of diamines. In particular, several synthetic pathways of 1,6-diaminohexane have been proposed based on glutamate or adipic acid. Here, we reviewed approaches for the biosynthesis of diamines, including metabolic engineering and biocatalysis, and the application of bio-based diamines in nylon materials. The related challenges and opportunities in the development of renewable bio-based diamines and nylon materials are also discussed.
Topics: Bacteria; Biocatalysis; Biosynthetic Pathways; Diamines; Metabolic Engineering; Nylons
PubMed: 32978133
DOI: 10.1128/AEM.01972-20 -
International Journal of Molecular... Nov 2023Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high... (Review)
Review
Polyamines (Pas) are short molecules that exhibit two or three amine groups that are positively charged at a physiological pH. These small molecules are present in high concentrations in a wide variety of organisms and tissues, suggesting that they play an important role in cellular physiology. Polyamines include spermine, spermidine, and putrescine, which play important roles in age-related diseases that have not been completely elucidated. Aging is a natural process, defined as the time-related deterioration of the physiological functions; it is considered a risk factor for degenerative diseases such as cardiovascular, neurodegenerative, and musculoskeletal diseases; arthritis; and even cancer. In this review, we provide a new perspective on the participation of Pas in the cellular and molecular processes related to age-related diseases, focusing our attention on important degenerative diseases such as Alzheimerߣs disease, Parkinsonߣs disease, osteoarthritis, sarcopenia, and osteoporosis. This new perspective leads us to propose that Pas function as novel biomarkers for age-related diseases, with the main purpose of achieving new molecular alternatives for healthier aging.
Topics: Polyamines; Spermidine; Spermine; Putrescine
PubMed: 38003659
DOI: 10.3390/ijms242216469 -
Oral Health & Preventive Dentistry Nov 2022To determine the salivary flow rate and subsequent dilution of toothpaste and assess the pH of oral fluids during toothbrushing with toothpastes of various pHs. (Clinical Trial)
Clinical Trial
PURPOSE
To determine the salivary flow rate and subsequent dilution of toothpaste and assess the pH of oral fluids during toothbrushing with toothpastes of various pHs.
MATERIALS AND METHODS
The study was conducted as an in-vivo trial involving 30 healthy volunteers. The participants took part in a series of trials distributed over four appointments. After a screening check, in which the participants' stimulated and unstimulated salivary flow rate and buffering capacities were determined, four test series involving toothbrushing were conducted. Participants brushed their teeth using a manual toothbrush for 2 min: once without toothpaste and three times using toothpastes of varying pHs. The salivary flow rate and subsequent dilution of the toothpaste was determined. Additionally, the pH of the collected oral fluid was analysed.
RESULTS
Brushing teeth with toothpaste caused a statistically significant increase in salivary flow rate (median/IQR in ml/min) (Elmex Kariesschutz 3.29/1.36, Colgate Total Original 3.23/1.08, Elmex Sensitive Professional 3.18/1.39) when compared to brushing teeth using a manual toothbrush without toothpaste (1.85/0.78) (p < 0.05). The variation in pH of the oral fluid samples was dictated primarily by the pH of the toothpaste used.
CONCLUSION
The salivary flow rate when brushing using toothpaste was similar across all tested toothpastes, independent of pH, and had an average median of 3.23 ml/min. The dilution of 1 g of toothpaste during a standard toothbrushing procedure of 2 min is therefore approximately at a ratio of one part toothpaste to 6.5 parts saliva.
Topics: Humans; Diamines; Fluorides; Toothbrushing; Toothpastes
PubMed: 36416604
DOI: 10.3290/j.ohpd.b3601691 -
The Journal of Biological Chemistry Dec 2020Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause... (Review)
Review
Mitochondrial DNA (mtDNA) encodes proteins and RNAs that support the functions of mitochondria and thereby numerous physiological processes. Mutations of mtDNA can cause mitochondrial diseases and are implicated in aging. The mtDNA within cells is organized into nucleoids within the mitochondrial matrix, but how mtDNA nucleoids are formed and regulated within cells remains incompletely resolved. Visualization of mtDNA within cells is a powerful means by which mechanistic insight can be gained. Manipulation of the amount and sequence of mtDNA within cells is important experimentally and for developing therapeutic interventions to treat mitochondrial disease. This review details recent developments and opportunities for improvements in the experimental tools and techniques that can be used to visualize, quantify, and manipulate the properties of mtDNA within cells.
Topics: Antibodies; Benzothiazoles; DNA, Mitochondrial; Diamines; Humans; In Situ Hybridization, Fluorescence; Microscopy, Confocal; Mitochondria; Quinolines; Urea
PubMed: 33454000
DOI: 10.1074/jbc.REV120.015101 -
Nature Communications Aug 2022Molecular conformations induced by the rotation about single bonds play a crucial role in chemical transformations. Revealing the relationship between the conformations...
Molecular conformations induced by the rotation about single bonds play a crucial role in chemical transformations. Revealing the relationship between the conformations of chiral catalysts and the enantiodiscrimination is a formidable challenge due to the great difficulty in isolating the conformers. Herein, we report a chiral catalytic system composed of an achiral catalytically active unit and an axially chiral 1,1'-bi-2-naphthol (BINOL) unit which are connected via a C-O single bond. The two conformers of the catalyst induced by the rotation about the C-O bond, are determined via single-crystal X-ray diffraction and found to respectively lead to the formation of highly important axially chiral 1,1'-binaphthyl-2,2'-diamine (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives in high yields (up to 98%), with excellent enantioselectivities (up to 98:2 e.r.) and opposite absolute configurations. The results highlight the importance of conformational dynamics of chiral catalysts in asymmetric catalysis.
Topics: Catalysis; Crystallography, X-Ray; Diamines; Molecular Conformation
PubMed: 35961985
DOI: 10.1038/s41467-022-32432-8 -
Chimia Apr 2020Polyoxophosphates are ubiquitous in nature and play important roles in biological systems and in the environment. Pyrophosphate (PPi), an important member of this... (Review)
Review
Polyoxophosphates are ubiquitous in nature and play important roles in biological systems and in the environment. Pyrophosphate (PPi), an important member of this family, is produced in over 200 biochemical reactions and is a marker in clinical diagnosis. In addition to its endogenous role, PPi alias E450 is currently used as preservative, emulsifier or taste intensifier in foodstuff. Despite this widespread occurrence and biological importance, it is rather surprising that robust chemical systems that detect selectively and sensitively PPi in challenging matrices are still lacking. This mini review focuses on metal-salen complexes as reaction-based fluorescent sensors for the selective detection of PPi and other phosphates. The mode of detection is based on a novel disassembly approach in which the metal ion is sequestered by the target analyte from the complex and the metal-free ligand hydrolyses spontaneously into its fluorescent subunits. Optimizations of the probe and applications for PPi detection in cells and foodstuff are described.
Topics: Ethylenediamines; Fluorescent Dyes; Metals; Phosphates
PubMed: 32331542
DOI: 10.2533/chimia.2020.252